tbuckley/cabot-search huggingface dataset:
Virus specific CD8+ T-cells accumulate, but do not recognize antigen, in the atherosclerotic lesion
Authors: M De Jong, MAC Depuydt, F Lozano Vigario, PA Van Veelen, J Kuiper, BA Slutter
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): ERA CVD Dutch Heart Foundation Viral infections have been associated with the progression of atherosclerosis. CD8+ T-cells directed against common viruses, such as influenza and Epstein-Barr virus, have been detected inside of human atherosclerotic lesions. These virus specific CD8+ T-cells have been hypothesized to contribute to the development of atherosclerosis, however, their mechanism of action in the atherosclerotic lesion remains unclear. This study aimed to characterize the behavior of virus specific CD8+ T-cells in the atherosclerotic lesion. The presence of virus specific CD8+ T-cells in atherosclerotic lesions was assessed by performing T-cell receptor (TCR)-β sequencing on human endarterectomy samples and patient matched blood samples (N=10). These TCRs were subsequently compared to known virus specific TCR sequences. Virus specific CD8+ T-cells seemed to accumulate in the atherosclerotic lesion (mean=3.5%), compared to patient matched blood samples (mean=2.0%) (p=0.053). Moreover, these virus specific CD8+ T-cells produced significantly more IFN-γ (p=0.0009) and Granzyme B (p=0.0038) in response to external stimuli, suggesting these T-cells may play a pro-inflammatory role in the pathogenesis of atherosclerosis. To investigate if virus specific CD8+ T-cells can be stimulated in situ, the immunopeptidome of 51 pooled human plaques was determined and matched with various viral peptidomes. Only one peptide presented in the atherosclerotic lesions matched a viral peptidome, rendering almost all virus specific CD8+ T-cells in the lesion antigen non-specific. In conclusion, virus specific CD8+ T-cells are enriched in atherosclerotic lesions and have an activated phenotype, compared to other plaque residing CD8+ T-cells. The absence of virus specific antigen presentation in the atherosclerotic lesion suggests that if these CD8+ T-cells contribute to inflammation, they do so in an antigen independent manner.
The key role of concomitant androgen-deprivation therapy on the efficacy of imaging guided treatments in men with biochemical recurrent prostate cancer after radical prostatectomy and 68Ga-PSMA PET/CT scan
Authors: D. Robesti, E. Mazzone, G. Gandaglia, A. Stabile, G. Rosiello, C.A. Bravi, A. Martini, G.O. Cirulli, A. Pellegrino, M. De Angelis, A. Necchi, D. Raggi, V. Cucchiara, N. Suardi, S. Shariat, F. Montorsi, A. Briganti
Journal: European Urology (2022)
LGG-54. Asthma reduces glioma formation by T cell decorin-mediated inhibition of microglia
Authors: Jit Chatterjee, Shilpa Sanapala, Olivia Cobb, Alice Bewley, Elizabeth Cordell, Joel Garbow, Michael Holtzman, David Gutmann
Journal: Neuro-Oncology (2022)

Abstract To elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage optic pathway glioma (Nf1-OPG) mice, human and mouse RNAseq data, and two different experimental asthma models. Following ovalbumin or house dust mite asthma induction at 4-6 weeks of age (WOA), Nf1-OPG mouse optic nerve volumes and proliferation are decreased at 12 and 24 WOA, indicating no tumor development. This inhibition is accompanied by reduced expression of the microglia-produced optic glioma mitogen, Ccl5. Human and murine T cell transcriptome analyses reveal that inhibition of microglia Ccl5 production results from increased T cell expression of decorin, which blocks Ccl4-mediated microglia Ccl5 expression through reduced microglia NFκB signaling. Decorin or NFkB inhibitor treatment of Nf1-OPG mice at 4-6 WOA inhibits tumor formation at 12 WOA, thus establishing a potential mechanistic etiology for the attenuated glioma incidence observed in children with asthma.
Clinical experiences with venetoclax and other pro-apoptotic agents in lymphoid malignancies: lessons from monotherapy and chemotherapy combination
Authors: Thomas E. Lew, John F. Seymour
Journal: Journal of Hematology & Oncology (2022)

Abstract BH3-mimetics are a novel drug class of small molecule inhibitors of BCL2 family proteins which restore apoptosis in malignant cells. The only currently approved BH3-mimetic, the selective BCL2 inhibitor venetoclax, is highly efficacious in chronic lymphocytic leukemia and has rapidly advanced to an approved standard of care in frontline and relapsed disease in combination with anti-CD20 monoclonal antibodies. In this context, tumour lysis syndrome and myelosuppression are the most commonly encountered toxicities and are readily manageable with established protocols. Venetoclax is active in other lymphoid malignancies including several B cell non-Hodgkin lymphomas, acute lymphoblastic leukemia and multiple myeloma, with the highest intrinsic sensitivity observed in mantle cell lymphoma and Waldenstrom macroglobulinemia. Venetoclax combination with standard regimens in follicular lymphoma, multiple myeloma and aggressive B cell neoplasms has shown some promise, but further studies are required to optimize dose and scheduling to mitigate increased myelosuppression and infection risk, and to find validated biomarkers of venetoclax sensitivity. Future research will focus on overcoming venetoclax resistance, targeting other BCL2 family members and the rational design of synergistic combinations.
Associations between integrase strand-transfer inhibitors and cardiovascular disease in people living with HIV: a multicentre prospective study from the RESPOND cohort consortium
Authors: Bastian Neesgaard, Lauren Greenberg, Jose M Miró, Katharina Grabmeier-Pfistershammer, Gilles Wandeler, Colette Smith, Stéphane De Wit, Ferdinand Wit, Annegret Pelchen-Matthews, Cristina Mussini, Antonella Castagna, Christian Pradier, Antonella d'Arminio Monforte, Jörg J Vehreschild, Anders Sönnerborg, Alain V Anne, Andrew Carr, Loveleen Bansi-Matharu, Jens D Lundgren, Harmony Garges, Felipe Rogatto, Robert Zangerle, Huldrych F Günthard, Line D Rasmussen, Coca Necsoi, Marc van der Valk, Marianna Menozzi, Camilla Muccini, Lars Peters, Amanda Mocroft, Lene Ryom
Journal: The Lancet HIV (2022)
Axillary pathologic response after neoadjuvant chemotherapy and surgery according to breast cancers subtypes and survival impact.
Authors: Eloise Michel, Laura Vincent, Françoise Beltjens, Laurent Arnould, Sylvain Ladoire, Charles Coutant, Clémentine Jankowski
Journal: Journal of Clinical Oncology (2022)

e12595 Background: The rate of pathologic complete response in the axilla (pCRAx) according to breast cancer biologic subtypes and the impact of nodal response on survival are lacking. Methods: Inclusion criteria were all T-stage breast cancers with initial lymph node involvement (determined by clinical palpation and radiological assessment by ultrasound and/or 18F-FDG PET scan), non-metastatic, treated with neoadjuvant chemotherapy followed by surgery with axillary lymph node dissection, managed at the George-François Leclerc Cancer Center in Dijon, France, between 2000 and 2018. pCRAx was defined as the absence of invasive cells in the axillary lymph nodes ( i.e. ypN0). The Sataloff classification was used as reference on each pathological report. Patients with a Sataloff NA classification ( i.e. evidence of therapeutic effect, and no residual disease) were classified as having pCRAx. Univariate and multivariate analysis were performed to identify factors predictive of pCRAx. Then, we analysed recurrence-free survival (RFS) and overall survival (OS) according to the type of nodal response of the different tumor subtypes. Survival curves were constructed using the Kaplan Meier method and compared using the log rank test. Results: Among 437 patients included, 227 (52%) were pathologically proven node-positive disease by biopsy. pCRAx rate was 35% (n=153) but varied according to tumor subtypes: 69.4% in HR(Hormone Receptor)-/HER2-positive, 47.4% in HR-/HER2-negative, 46.7% in HR+/HER2-positive, 8.5% in HR+/HER2-negative. By multivariate analysis, the factors significantly associated with pCRAx were HER2-positive profile (OR 4.48 (2.14-9.65), p&lt;0.001 if HR+; OR 8.02 (3.54-18.74), p&lt;0.001 if HR-), triple negative tumors (OR 3.01; 95%CI [1.40-6.58], p=0.005), Scarff-Bloom-Richardson III grade (OR 7.05; 95%CI [2.35-30.41], p=0.002) and breast complete response (OR 18.69; 95%CI [9.67-38.53], p&lt;0.001). Ten-year recurrence rates were 19.6% in ypN0, 30.4% in ypN1, 49.5% in ypN2, 61.5% in ypN3 patients ( p&lt;0.001). pCRAx has a prognostic impact on RFS regardless of the tumor subtype. Ten-year overall survival rates were 87.6% in ypN0, 79.5% in ypN1, 58.8% in ypN2, 42.3% in ypN3 patients ( p&lt;0.001). In subgroup analysis, pCRAx had an impact on OS for all tumor subtypes except HR+/HER2-positive tumors. Conclusions: Breast cancer is a heterogeneous disease in which pCRAx rates vary according to breast cancer subtypes. The impact of nodal response on survival was significant. With pCRAx rates ranging from 46% to almost 70% for the HR-/HER2-negative and HER2-positive tumors, pCRAx appears to be a good surrogate marker of long-term outcome in patients treated for these cancers.
Utility of adjuvant chemotherapy in early-stage, estrogen receptor-positive breast cancer patients under 50 years with a 21-gene recurrence-score of 16-25: A retrospective analysis using the National Cancer Database.
Authors: Prashanth Ashok Kumar, Dongliang Wang, Danning Huang, Abirami Sivapiragasam
Journal: Journal of Clinical Oncology (2022)

e12501 Background: The TAILORx trial showed that addition of adjuvant chemotherapy (AC) to endocrine therapy (ET) had no advantage in estrogen receptor (ER)+, HER2-, node negative (N0) breast cancer (BC) patients with an intermediate (11-25) 21-gene recurrence-score (RS). However, a subgroup analysis revealed that in women ≤ 50 years, AC had a lower rate of distant recurrence if the RS was 16-25. Using a large national database, we studied the utilization of AC in the aforementioned subset. Methods: The 2004-2018 National Cancer Database BC cohort was used to include female patients of 18-50 years. Inclusion criteria were N0, M0 patients with any T stage, RS 16-25, ER+/PR± and HER2-. Patients who received neoadjuvant chemotherapy were excluded. Logistic regression was used to evaluate AC utility trends. Kaplan-Meier (KM) and multivariate (MV) propensity score (PS) weighted Cox model were used to compare survival between patients without and with AC use. Results: Of the 15,792 patients, 4808 (30.45%) received AC. Median RS was 18 and 21 in patients without and with AC. Factors associated with AC use were higher T stage, poor and moderately differentiated tumors, age &lt;40, care at an academic center, Caucasian race, patients undergoing mastectomy, regional lymph node (RLN) surgery, ET and Radiation Therapy (RT). KM survival at 10 years was better with AC [96.2% vs 91.6%]. Patients without AC had worse survival [Hazard Ratio (HR)=1.683, 95% Confidence Interval (CI): 1.392-2.036, p&lt;0.0001] (Table). Conclusions: In this analysis,AC use had a 5% improvement in 10 year overall survival, in contrast to TAILORx trial which only showed a disease free survival benefit. Whether the benefit was due to direct cytotoxicity or ovarian function suppression effect of AC remains to be seen. In clinical practice, AC use is determined based on patient and tumor characteristics. Limitations of our study include non-population-based data and the possibility of cofounding despite the use of PS matching. [Table: see text]
A randomized phase Ib/II study of niraparib (nira) plus nivolumab (nivo) or ipilimumab (ipi) in patients (pts) with platinum-sensitive advanced pancreatic cancer (aPDAC).
Authors: Kim Anna Reiss, Rosemarie Mick, Ursina R. Teitelbaum, Mark H. O'Hara, Charles John Schneider, Ryan Campbell Massa, Thomas Benjamin Karasic, Chioma Onyiah, Mary Kate Gosselin, Alyssa Donze, Susan M. Domchek, Robert H. Vonderheide
Journal: Journal of Clinical Oncology (2022)

4021 Background: Establishing alternatives to perpetual chemotherapy for pts with aPDAC has been proposed to address inevitable chemotherapy resistance and cumulative toxicity. Poly (ADP ribose) polymerase (PARP) inhibitors have shown clinical efficacy in this setting, and preclinical data suggest that the addition of immune checkpoint blockade (ICB) may offer synergistic tumor control. We performed a randomized, phase Ib/II study of nira plus anti-PD-1 (nivo) or nira plus anti-CTLA-4 (ipi) maintenance for pts with aPDAC who had not progressed after &gt;4 mo of platinum-based therapy. Methods: After discontinuation of chemotherapy, pts were randomized 1:1 to nira 200mg PO daily plus either nivo 240mg IV q2 weeks (later amended to 480mg IV q4 weeks) or ipi 3mg/kg IV q3 weeks for four doses. Nira could be escalated to 300mg PO daily if tolerated. Pts were treated until progression or unacceptable toxicity. The primary endpoint was progression free survival at six months (PFS6) in each arm. Secondary endpoints included safety, OS, ORR, and outcomes by DNA damage repair (DDR) deficiencies. Pts were evaluable for safety if they had received &gt; 1 dose of study treatment and for efficacy if they had also received &gt; 1 follow-up imaging study. Based on historical data, the null hypothesis of PFS6 = 44% vs a 2-sided alternative hypothesis of PFS ≠ 44% was tested. 42 pts per arm provided 81% power for testing at a 5% significance level to detect inferior PFS6 &lt; 27% or superior PFS6 &gt; 61%. Results: As of Oct 2021, 91 pts were enrolled, of whom 84 were evaluable for efficacy (44 nira/nivo; 40 nira/ipi). The median potential follow-up was 23 mos. Most common treatment-related AEs were nira/nivo: thrombocytopenia (28%), arthralgia (25%), nausea (23%), and fatigue (23%) and nira/ipi: thrombocytopenia (45%), anemia (43%), fatigue (43%), nausea, (41%), AST increase (36%), rash (34%) and ALT increase (29%). 88% of AEs were grade 1-2. Efficacy results were: nira/nivo: PFS6 20.6% (95% CI 8.3-32.9, p = 0.0002), mPFS 1.9 mo and nira/ipi: PFS6 59.6% (95% CI 44.3-74.9, p = 0.045), mPFS 8.1 mo. Fifteen pts (8 nira/nivo; 7 nira/ipi) had pathogenic variants in BRCA or PALB2 . Excluding these: mPFS on nira/nivo was 1.9 mo (95% CI 1.8-1.9) and mPFS on nira/ipi was 7.6 mo (95% CI 4.0 – 11.1). Conclusions: In a randomized phase 1B/II study, nira/ipi as maintenance therapy met the primary endpoint of superior PFS6 while nira/nivo yielded inferior PFS6 for pts with aPDAC who had not progressed on first-line platinum-based chemotherapy. The benefit of nira/ipi maintenance persisted in pts without known DDR variants. Clinical trial information: NCT03404960. [Table: see text]
Neuronal NLRP3 is a parkin substrate that drives neurodegeneration in Parkinson’s disease
Authors: Nikhil Panicker, Tae-In Kam, Hu Wang, Stewart Neifert, Shih-Ching Chou, Manoj Kumar, Saurav Brahmachari, Aanishaa Jhaldiyal, Jared T. Hinkle, Fatih Akkentli, Xiaobo Mao, Enquan Xu, Senthilkumar S. Karuppagounder, Eric T. Hsu, Sung-Ung Kang, Olga Pletnikova, Juan Troncoso, Valina L. Dawson, Ted M. Dawson
Journal: Neuron (2022)
Association between platelets and in-hospital mortality in critically ill patients with tumors: A retrospective cohort study.
Authors: Zhao Chaofen
Journal: Journal of Clinical Oncology (2022)

e18552 Background: Platelet count is an independent predictor of mortality in cancer patients. It remains unknown whether the platelet count is related to in-hospital mortality in severely ill patients with tumours. Methods: A retrospective study based on a dataset from a multicentre cohort. Setting This was a secondary analysis of data from one Electronic Intensive Care Unit (eICU) Collaborative Research Database (eICU- CRD) survey cycle (2014-2015). Participants The data pertaining to severely ill patients with tumours were collected from 208 hospitals located across the United States. This study initially a total of 200859 participants. After the population was limited to patients with combined tumours and platelet deficiencies, the remaining 2628 people were included in the final data analysis. Primary and secondary outcome measures The main measure was the platelet count, and the main outcome was in-hospital mortality. Results: After adjustment for the covariates, the platelet count had a curvilinear relationship with in-hospital mortality (P &lt; 0.001). The first inflection point was 18.4 (per 10 change). On the left side of the first inflection point (platelet count ≤ 184 K/mcL), an increase of 10 in the platelet count was negatively associated with in-hospital mortality [OR = 0.92, 95% CI = 0.89 to 0.95, P &lt; 0.001]. The second inflection point was 44.5 (per 10 change). Additional increases of 10 in the platelet count thereafter were positively associated with hospital mortality [OR = 1.13, 95% CI = 1.00 to 1.28, P = 0.0454]. The baseline platelet count was in the range of 184 K/mcL to 445 K/mcL(P = 0.0525), and the hospital mortality was lower than the baseline platelet count in other ranges. Conclusions: The relationship between platelet count and in-hospital mortality in critically ill patients with tumours was curvilinear. The lowest in-hospital mortality was associated with platelet count between 184 K/mcL and 445 K/mcL. This indicates that both high and low platelet count should receive attention in clinical practice.
Communication about cost of cancer care: Attitudes and practices of oncologists.
Authors: Ahmed Bilal Khalid, Samuel Urrutia, Nasser H. Hanna
Journal: Journal of Clinical Oncology (2022)

e18826 Background: With the cost of cancer care rising, it is becoming ever so important for physicians to be mindful of financial toxicity to their patients. Patient-provider cost discussions are associated with lower out of pocket costs (Hong el al, Value in Health 2020), yet few patients report having this discussion with their physician. There are few reports on oncologist’s preparedness, current practice, and barriers in discussing costs with their patients. Methods: An online survey was administered to hematology/oncology faculty physicians and fellows at the IU Simon Comprehensive Cancer Center. The objectives were to assess attitudes on communication about cost of cancer care and awareness around financial toxicity of cancer therapy. The questions included physician perception on patient’s attitudes towards cost discussion in clinics, current state of cost discussion in their clinic and their preparedness on having this discussion in the future. Results: 27/48 (56%) fellows and faculty members completed the survey. All respondents believed cost communication is associated with improved patient outcomes and 82% believed cost communication is desired by most patients. 22/27 (81%) indicated cost of care were discussed in less than half of patient encounters. 22/27 (81%) believed clear communication about cost should be a part of the patient’s clinic visit. When asked to rate their preparedness level on a scale of 0-100 on discussing cost of cancer care in their clinics, the median preparedness level was 20. Median awareness level about patient’s insurance plan was 20 and median awareness level about patient out of pocket cost was 21. 26/27 (96%) believed knowing cost of therapy and out of pocket cost would change the way they practice. 20/27 (74%) reported that not knowing the cost of cancer care themselves was the greatest barrier behind not discussing costs. Conclusions: Despite believing cost of cancer care should be discussed in the clinic, most hematologists/oncologists surveyed did not do so. Physician education on cost of cancer care and patient out-of-pocket costs is greatly needed.
Author's correction for Euro Surveill. 2021;26(47)
Journal: Eurosurveillance (2022)

© This work is licensed under a Creative Commons Attribution 4.0 International License. Closure This is a corrected article applying to the following content: Estimated number of deaths directly averted in people 60 years and older as a result of COVID-19 vaccination in the WHO European Region, December 2020 to November 2021
RARE-14. Newborn with hypothalamic hamartoma and Pallister-Hall syndrome
Authors: Anna Meera Flaßkühler, Carsten Friedrich, Julia Beckhaus, Svenja Boekhoff, Kai Fiedler, Mechthild Schulze Becking, Marc-Philipp Hitz, Laura Gieldon, Stephanie Spranger, Brigitte Bison, Florian Hoppe, Hermann L Müller
Journal: Neuro-Oncology (2022)

Abstract A female full-term newborn of 41 + 2 weeks gestational age with a respiratory adaptation disorder and hypercapnia was transferred from an external maternity clinic to our pediatric intensive care unit. The child is the second child of healthy, non-consanguineous parents. Multiple dysmorphias were noticed at arrival. We identified a choanal atresia/stenosis on both sides in the respiratory tract, a high palate, a submucous cleft palate, a bifid uvula, a laryngeal cleft and a bronchus suis. The child required intubation and ventilation. In addition, we recognized brachydactyly of the hands and feet. The phalanges were not visibly separable. There was nail hypoplasia and rocker bottom feet on both sides. Furthermore, we saw an anal atresia. In routine laboratory work-up, a hypoglycemia and not measurable low TSH serum concentration was noticed. Extended endocrinological laboratory diagnostics revealed a complete pituitary insufficiency. On cranial MRI, a large, iso- to slightly hyperintense space-occupying mass (3.8x3.7x2.5 cm3), originating from the hypothalamus was observed. The brainstem was displaced posteriorly by the mass. The imaging is consistent with a hypothalamic hamartoma. With regard to the present findings, we assumed an underlying genetic cause of the congenital malformations. As a clinical diagnosis, a Pallister-Hall syndrome was suspected. As described in our case, we saw the characteristic features: dysmorphia of the hands and feet, upper respiratory tract, anal atresia, and hypothalamic hamartomas. The Pallister-Hall syndrome is caused by mutations in the GLI3 gene on the 7p13 chromosome. It is inherited in an autosomal dominant manner and its prevalence is unknown. In our patient, a heterozygous, probably pathogenic variant in the GLI3-Gene was proven by Next Generation Sequencing (NGS).
Perspectives on the Risk-Stratified Treatment of Multiple Myeloma
Authors: Faith E. Davies, Charlotte Pawlyn, Saad Z. Usmani, Jesus F. San-Miguel, Hermann Einsele, Eileen M. Boyle, Jill Corre, Daniel Auclair, Hearn Jay Cho, Sagar Lonial, Pieter Sonneveld, A. Keith Stewart, P. Leif Bergsagel, Martin F. Kaiser, Katja Weisel, Jonathan J. Keats, Joseph R. Mikhael, Kathryn E. Morgan, Irene M. Ghobrial, Robert Z. Orlowski, C. Ola Landgren, Francesca Gay, Joseph Caers, Wee Joo Chng, Ajai Chari, Brian A. Walker, Shaji K. Kumar, Luciano J. Costa, Kenneth C. Anderson, Gareth J. Morgan
Journal: Blood Cancer Discovery (2022)

Summary: The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.